Disrupted BMP-9 Signaling Impairs Pulmonary Vascular Integrity in Hepatopulmonary Syndrome
RATIONALE: Hepatopulmonary syndrome (HPS) is a severe complication of liver diseases characterized by abnormal dilatation of pulmonary vessels, resulting in impaired oxygenation. Recent research highlights the pivotal role of liver-produced bone morphogenetic protein (BMP)-9 in maintaining pulmonary vascular integrity.
OBJECTIVES: This study aimed to investigate the involvement of BMP-9 in human and experimental HPS.
METHODS: Circulating BMP-9 levels were measured in 63 healthy controls and 203 cirrhotic patients, with or without HPS. Two animal models of portal hypertension were employed: common bile duct ligation (CBDL) with cirrhosis and long-term partial portal vein ligation (PPVL) without cirrhosis. Additionally, the therapeutic effect of low-dose BMP activator FK506 was investigated, and the pulmonary vascular phenotype of BMP-9 knockout rats was analyzed.
MEASUREMENTS AND MAIN RESULTS: Patients with HPS related to compensated cirrhosis demonstrated lower levels of circulating BMP-9 compared to patients without HPS. Severe cirrhosis patients exhibited consistently low levels of BMP-9. In animal models, HPS characteristics, including intrapulmonary vascular dilations (IPVDs) and alveolo-arterial gradient enlargement, were observed. HPS development in both rat models correlated with reduced intrahepatic BMP-9 expression, decreased circulating BMP-9 level and activity, and impaired pulmonary BMP-9 endothelial pathway. Daily treatment with FK506 for 2-weeks restored BMP pathway in the lungs, alleviating IPVDs, and improving gas exchange impairment. Furthermore, BMP-9 knockout rats displayed a pulmonary HPS phenotype, supporting its role in disease progression.
CONCLUSION: The study findings suggest that portal hypertension-induced loss of BMP-9 signaling contributes to HPS development.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - year:2024 |
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| Enthalten in: |
American journal of respiratory and critical care medicine - (2024) vom: 16. Apr. |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Robert, Fabien [VerfasserIn] |
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| Links: |
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| Themen: |
BMP-9 |
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| Anmerkungen: |
Date Revised 22.04.2024 published: Print-Electronic Citation Status Publisher |
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| doi: |
10.1164/rccm.202307-1289OC |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM371154197 |
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| 245 | 1 | 0 | |a Disrupted BMP-9 Signaling Impairs Pulmonary Vascular Integrity in Hepatopulmonary Syndrome |
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| 520 | |a RATIONALE: Hepatopulmonary syndrome (HPS) is a severe complication of liver diseases characterized by abnormal dilatation of pulmonary vessels, resulting in impaired oxygenation. Recent research highlights the pivotal role of liver-produced bone morphogenetic protein (BMP)-9 in maintaining pulmonary vascular integrity | ||
| 520 | |a OBJECTIVES: This study aimed to investigate the involvement of BMP-9 in human and experimental HPS | ||
| 520 | |a METHODS: Circulating BMP-9 levels were measured in 63 healthy controls and 203 cirrhotic patients, with or without HPS. Two animal models of portal hypertension were employed: common bile duct ligation (CBDL) with cirrhosis and long-term partial portal vein ligation (PPVL) without cirrhosis. Additionally, the therapeutic effect of low-dose BMP activator FK506 was investigated, and the pulmonary vascular phenotype of BMP-9 knockout rats was analyzed | ||
| 520 | |a MEASUREMENTS AND MAIN RESULTS: Patients with HPS related to compensated cirrhosis demonstrated lower levels of circulating BMP-9 compared to patients without HPS. Severe cirrhosis patients exhibited consistently low levels of BMP-9. In animal models, HPS characteristics, including intrapulmonary vascular dilations (IPVDs) and alveolo-arterial gradient enlargement, were observed. HPS development in both rat models correlated with reduced intrahepatic BMP-9 expression, decreased circulating BMP-9 level and activity, and impaired pulmonary BMP-9 endothelial pathway. Daily treatment with FK506 for 2-weeks restored BMP pathway in the lungs, alleviating IPVDs, and improving gas exchange impairment. Furthermore, BMP-9 knockout rats displayed a pulmonary HPS phenotype, supporting its role in disease progression | ||
| 520 | |a CONCLUSION: The study findings suggest that portal hypertension-induced loss of BMP-9 signaling contributes to HPS development | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a BMP-9 | |
| 650 | 4 | |a Cirrhosis | |
| 650 | 4 | |a Hepatopulmonary syndrome | |
| 650 | 4 | |a Intrapulmonary vascular dilatations | |
| 650 | 4 | |a Portal hypertension | |
| 700 | 1 | |a Certain, Marie-Caroline |e verfasserin |4 aut | |
| 700 | 1 | |a Baron, Audrey |e verfasserin |4 aut | |
| 700 | 1 | |a Thuillet, Raphaël |e verfasserin |4 aut | |
| 700 | 1 | |a Duhaut, Léa |e verfasserin |4 aut | |
| 700 | 1 | |a Ottaviani, Mina |e verfasserin |4 aut | |
| 700 | 1 | |a Kamel Chelgham, Mustapha |e verfasserin |4 aut | |
| 700 | 1 | |a Normand, Corinne |e verfasserin |4 aut | |
| 700 | 1 | |a Berrebeh, Nihel |e verfasserin |4 aut | |
| 700 | 1 | |a Ricard, Nicolas |e verfasserin |4 aut | |
| 700 | 1 | |a Furlan, Valerie |e verfasserin |4 aut | |
| 700 | 1 | |a Desroches-Castan, Agnès |e verfasserin |4 aut | |
| 700 | 1 | |a Gonzales, Emmanuel |e verfasserin |4 aut | |
| 700 | 1 | |a Jacquemin, Emmanuel |e verfasserin |4 aut | |
| 700 | 1 | |a Sitbon, Olivier |e verfasserin |4 aut | |
| 700 | 1 | |a Humbert, Marc |e verfasserin |4 aut | |
| 700 | 1 | |a Bailly, Sabine |e verfasserin |4 aut | |
| 700 | 1 | |a Coilly, Audrey |e verfasserin |4 aut | |
| 700 | 1 | |a Guignabert, Christophe |e verfasserin |4 aut | |
| 700 | 1 | |a Tu, Ly |e verfasserin |4 aut | |
| 700 | 1 | |a Savale, Laurent |e verfasserin |4 aut | |
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